I. Field of the Invention
The present invention relates to the fields of medicine, pathology and molecular biology.
More particular the invention relates to the role of neprilysin in pulmonary hypertension and chronic obstructive pulmonary disease (COPD), and methods of using neprilysin to diagnose and treat these diseases.
II. Related Art
Chronic obstructive pulmonary disease (COPD) is a leading cause of death; cigarette smoking is its primary risk factor (Churg et al., 2008). Pulmonary vascular remodeling, characterized by thickening, muscularization, and rarification of the distal vasculature (Rabinovitch, 2008; Preston, 2007; Peinado et al., 2008), complicates COPD by contributing to pulmonary hypertension (PHTN) (Preston, 2007; Jeffery, 2001). Many COPD patients have mild PHTN at rest (Steiner, 2009; Naeije and Barbera, 2001; Thabut et al., 2005); however, the prevalence of exercise-induced PHTN, which also may lead to right heart failure in COPD (Weitzenblum et al., 2009), is much higher (over 91%; Steiner, 2009; Kubo et al., 2000).
COPD-associated PHTN is likely caused by initial injury of the pulmonary vascular endothelium by cigarette smoke (CS) (Peinado et al., 2008), followed by inflammation and hypoxia, all which may involve oxidant mechanisms (Dempsey et al., 1996; Kong et al., 2006). Factors that may contribute to variable susceptibility to COPD-associated PHTN, including interleukin-6 (IL-6) and the serotonin transporter (5HTT) (Steiner, 2009; Kubo et al., 2000; Chaouat et al., 2009; Ulrich et al., 2010), have been extensively investigated.
Neprilysin (NEP, CD10) is a transmembrane zinc peptidase that degrades specific peptides, and is widely expressed, including in pulmonary arterial (PA) SMCs, endothelial cells, and fibroblasts (Shipp et al., 1988; Sunday et al., 1992). NEP activity/expression is decreased by CS (Dusser et al., 1989), hypoxia (Dempsey et al., 2009; Carpenter and Stenmark, 2001), or reactive oxygen species (ROS) (Shinall et al., 2005). Hypoxic NEP null mice develop greater PHTN, and PA SMCs from these mice grow faster than those from wt mice, suggesting that NEP protects against chronic hypoxic PHTN, in part by suppressing PA SMC growth and migration (Dempsey et al., 2009). However, NEP's role in human pulmonary vascular remodeling complicating chronic lung disease, has not been investigated.